Low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas are extranodal B-cell lymphomas that arise in the context of chronic gastric inflammation induced by persistent Helicobacter pylori infection (Sagaert X. et al., Nat Rev Gastroenterol Hepatol 2010, 7(6):336-346). In its early stages, MALT lymphoma is an indolent and localized disease that can be treated by antibiotic eradication therapy targeting the underlying infection. In line with the concept that gastric MALT lymphomas are antigen-driven tumors, the surface immunoglobulins of MALT lymphoma B-cells are clonal, somatically hypermutated, and have undergone positive selection. MALT lymphoma tumor immunoglobulins (Igs) are polyreactive, i.e. they bind with similar affinity to various unrelated self and foreign antigens, and show a biased use of Ig VH gene segments previously linked to poly- and autoreactive antibodies (Craig V. J. et al., Blood 115:581-591 (2010)). Early MALT lymphomas further require T-cell help in the form of soluble T-helper cell-derived signals, most likely B-cell mitogenic cytokines such as IL-4 and IL-5.
Low grade MALT lymphomas may progress to more advance disease, either through the acquisition of one of three characteristic chromosomal translocations resulting in the constitutive activation of the NE-KB signaling pathway, or through the histologically evident transformation to high-grade gastric diffuse large B-cell lymphoma (gDLBCL). High grade transformation of Helicobacter-associated MALT lymphoma accounts for the majority of gDLBCL cases, whereas primary gDLBCL is rare. gDLBCL is characterized by antigen-independent growth, resistance to Helicobacter eradication therapy and a number of genetic alterations that may contribute to high grade transformation. In particular, TP53 mutations, Bcl6 overexpression and the aberrant DNA hypermethylation of tumor suppressor genes have been shown to be associated with high grade transformation. However, the precise molecular mechanisms underlying the transition from low-grade MALT lymphoma to gDLBCL remain largely unclear.
MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs, which modulate the expression of their target genes at the post-transcriptional level. Aberrant expression of specific miRNAs has been associated with both solid and hematopoietic malignancies, including chronic lymphocytic leukemia, lung cancer and ovarian cancer. The majority of human miRNAs are located at fragile sites or cancer associated genomic regions. For example, the frequent down-regulation of the fragile region encoding miR-15a (microRNA-15a) and miR-16-1 promotes CLL through dysregulation of the Bcl2 oncogene. The widespread deregulation of the miRNA transcriptome appears to be a hallmark of cancer and has been attributed to deletions, amplifications or mutations of miRNA loci, epigenetic silencing or aberrant transcriptional regulation of miRNA genes. Many studies have revealed the potential of miRNA expression profiles as diagnostic and prognostic markers of cancers, which may be more useful than expression analysis of protein-coding genes for the classification and stratification of cancer subtypes (Zhang B. et al., Dev Biol 2007, 302(1):1-12).
MicroRNA profiling in Burkitt lymphoma demonstrated a very characteristic MYC induced microRNA expression. This indicates that MYC regulates Burkitt lymphoma cell fate in a direct mode at the transcription level and indirectly at the translational level (Robertus J. L. et al., Brit J Haematol 2010, 149:896-899). In chronic lymphocytic leukemia (CLL) patients with TP53 abnormalities exhibit downregulation of miR-34a, miR-29c and mirR-17-5p (Mraz M. et al., Leukemia 2009, 23:1159-63).